JP2020046240A - Ischemia time estimation method and ischemia time estimation device - Google Patents

Abstract

To provide a technology capable of estimating the ischemia time of an extracted organ.SOLUTION: An ischemia time estimation method includes: a process (step ST200-ST400) of perfusing a perfusing liquid containing a biomarker in an organ; a process (step ST300) of measuring the concentration of the biomarker contained in a discharge liquid discharged from the organ; a process (step ST500) of calculating the decrement of the biomarker on the basis of the measurement result of the concentration of the biomarker; and a process (step ST600) of estimating the ischemia time of the organ on the basis of the estimation function showing the relationship between the ischemia time and the decrement of the biomarker, and on the basis of the calculation result of the decrement of the biomarker.SELECTED DRAWING: Figure 3

Description

  The present invention relates to a method and an apparatus for estimating ischemia time of a removed organ.

  Conventionally, several methods have been known as methods for evaluating organs in a living body. As a conventional organ evaluation method, for example, Patent Document 1 discloses a liver disease marker and a method for measuring the same. According to the method described in Patent Literature 1, it is possible to estimate what kind of disease the liver in a living body has.

  On the other hand, when performing an organ transplant operation or conducting an experiment using an extracted organ, it is important to understand the ischemic time, external damage, internal damage, etc. of the extracted organ. It is.

JP 2011-232164 A

  However, a method for evaluating the condition of the removed organ has not been established. When an organ is removed, it may be transported to another facility or another room where a transplant operation is performed after the removal. In such a case, it is difficult to accurately grasp the ischemic time of the organ at the destination due to the state of the donor at the time of organ removal, the state of the organ during the organ removal operation, or the method of transportation. .

  On the other hand, depending on the length of ischemic time, the necessity of organ recovery treatment, compatibility with the recipient, and the survival rate of the organ differ. For this reason, it is preferable to grasp the ischemic time of the organ as accurately as possible.

  The present invention has been made in view of such circumstances, and has as its object to provide a technique capable of estimating the ischemic time of a removed organ.

  In order to solve the above problems, a first invention of the present application is an ischemia time estimation method for estimating an ischemia time of an isolated organ, wherein a) perfusing a perfusion solution containing a biomarker into the organ, b) measuring the concentration of the biomarker contained in the effluent discharged from the organ in the step a), and c) calculating the amount of decrease in the biomarker from the measurement result in the step b). , D) estimating the ischemia time of the organ from an estimation function indicating the relationship between the ischemia time and the decrease amount of the biomarker and the calculation result of the step c).

  The second invention of the present application is the method for estimating ischemia time according to the first invention, wherein before the step a), e) the biomarker is included for a plurality of the organs whose ischemia time is known. Perfusing a perfusate, f) measuring the concentration of the biomarker contained in the effluent discharged from each of the plurality of organs in the step e), and g) measuring the result of the step f) Calculating the amount of decrease in the biomarker for each of the plurality of organs, and h) calculating the estimation function from the relationship between the ischemic time of the plurality of organs and the amount of decrease in the biomarker. And calculating.

  A third invention of the present application is the ischemia time estimation method of the first invention or the second invention, wherein the organ is a liver, and the biomarker is indocyanine green.

  A fourth invention of the present application is the ischemia time estimation method of the third invention, wherein the ischemia time is a warm ischemia time.

  The fifth invention of the present application is the ischemia time estimation method of the third invention or the fourth invention, wherein the estimation function is a function in which the decrease amount of the biomarker increases as the ischemia time increases. is there.

  The sixth invention of the present application is the ischemia time estimation method according to any one of the third invention to the fifth invention, wherein the estimation function calculates the decrease amount of the biomarker by a linear function of the ischemia time. This is the function shown.

  A seventh invention of the present application is an ischemia time estimating device for estimating an ischemia time of an isolated organ, wherein the perfusion unit for perfusing a perfusion solution containing a biomarker into the organ, A measurement unit that measures the concentration of the biomarker contained in the discharged effluent, a reduction amount calculation unit that calculates the reduction amount of the biomarker from the measurement result of the measurement unit, the ischemic time and the biomarker And an ischemic time estimating unit for estimating the ischemic time of the organ from the estimation function indicating the relationship of the amount of decrease and the amount of decrease calculated by the amount of decrease calculation unit.

  An eighth invention of the present application is the ischemia time estimation device according to the seventh invention, wherein the organ is a liver, and the biomarker is indocyanine green.

  A ninth invention of the present application is the ischemia time estimation device of the eighth invention, wherein the ischemia time is a warm ischemia time.

  The tenth invention of the present application is the ischemia time estimation device of the eighth invention or the ninth invention, wherein the estimation function is a function in which the decrease amount of the biomarker increases as the ischemia time increases. is there.

  An eleventh invention of the present application is the ischemia time estimation device according to any one of the eighth invention to the tenth invention, wherein the estimation function calculates the amount of decrease in the biomarker by a linear function of the ischemia time. This is the function shown.

  According to the first to eleventh aspects of the present invention, it is possible to estimate the ischemic time of the removed organ.

  In particular, according to the third or eighth aspect of the present invention, it is possible to estimate the ischemic time of the extracted liver.

It is the schematic which showed the structure of the ischemic-time estimation apparatus which concerns on 1st Embodiment. FIG. 2 is a block diagram showing an electrical connection of the ischemia time estimation device according to the first embodiment. 4 is a flowchart illustrating a flow of an ischemia time estimation method according to the first embodiment. 5 is a graph illustrating an example of an estimation function in the ischemia time estimation method according to the first embodiment. FIG. 5 is a conceptual diagram showing a relationship between an elapsed time from the start of perfusion of a perfusion solution containing ICG and a decrease in ICG. It is a flowchart which shows the flow of the estimation function acquisition process contained in the ischemia time estimation method which concerns on 1st Embodiment. It is a graph which shows the estimation function in an experimental example.

  Hereinafter, embodiments of the present invention will be described with reference to the drawings. In the present application, “donor” and “recipient” may be a human or a non-human animal. That is, in the present application, the “organ” including the “liver” may be a human organ or a non-human animal organ. Further, the non-human animal may be a rodent including a mouse and a rat, an ungulate including a pig, a goat and a sheep, a non-human primate including a chimpanzee, and other non-human mammals. Other animals may be used.

<1. First Embodiment>
<1-1. Configuration of ischemia time estimation device>
An ischemic time estimation device 1 according to a first embodiment of the present invention will be described with reference to FIGS. FIG. 1 is a schematic diagram illustrating a configuration of the ischemia time estimation device 1. FIG. 2 is a block diagram showing an electrical connection of the ischemia time estimation device 1.

  As shown in FIG. 1, the ischemia time estimation device 1 includes a bioreactor region 10 in which the extracted liver 9 is stored, a perfusion unit 20, a measurement unit 30, an input display unit 70, and a control unit 80. Having.

  In the bioreactor region 10, a container capable of immersing at least a part of the liver 9 in a liquid such as a perfusion solution or a preservation solution is arranged.

  The perfusion unit 20 includes a perfusion solution reservoir 21, a perfusion solution supply pipe 22, a pump 23 inserted in the perfusion solution supply pipe 22, a deaeration unit 24, a pressure gauge 25 and a flow meter 26, and a first waste tank 27. And a pump 29 inserted into the perfusate discharge pipe 28.

  The perfusate reservoir 21 is a perfusate container in which the perfusate is stored. The perfusate stored in the perfusate reservoir 21 contains a biomarker, indocyanine green (hereinafter referred to as “ICG”), at a certain ratio. Specifically, the perfusate of the present embodiment contains albumin and ICG at a concentration of 4 mg / L, respectively. The perfusate may also include an oxygen carrier, such as red blood cells or artificial red blood cells.

  One end of the perfusate supply pipe 22 is connected to the perfusate reservoir 21, and the other end is connected to a blood vessel of the liver 9. Specifically, the other end of the perfusate supply pipe 22 is connected to the portal vein of the liver 9 or the hepatic artery. The pump 23 generates a flow of the perfusate from the perfusate reservoir 21 toward the liver 9 in the perfusate supply pipe 22. The deaeration unit 24 removes gas components contained in the perfusate flowing through the perfusate supply pipe 22. The pressure gauge 25 measures the pressure in the perfusate supply pipe 22. The flow meter 26 measures the flow rate of the perfusate in the perfusate supply pipe 22.

  The first waste tank 27 stores the perfusate discharged from the liver 9 (hereinafter referred to as “discharge”). One end of the perfusate discharge pipe 28 is connected to the blood vessel of the liver, and the other end is connected to the first waste tank 27. Specifically, one end of the perfusate drainage pipe 28 is connected to the upper hepatic inferior vena cava (SH-IVC) or the lower hepatic inferior vena cava (IH-IVC). The pump 29 generates a flow of the discharged liquid from the liver 9 to the first waste tank 27 in the perfusate discharged pipe 28.

  A three-way valve 281 is interposed between the pump 29 of the perfusate discharge pipe 28 and the first waste tank 27. The three-way valve 281 is connected to one end of a measurement pipe 31 of the measurement unit 30 described later. When the three-way valve 281 is in the normal state, the discharged liquid is directed from the liver 9 to the first waste tank 27. On the other hand, when the three-way valve 281 is in the measurement state, the discharged liquid is directed from the liver 9 to the second waste tank 32 of the measurement unit 30 described later.

  The measurement unit 30 includes a measurement pipe 31, a second waste tank 32, a filter 33, and an absorbance measurement unit 34.

  One end of the measurement pipe 31 is connected to the three-way valve 281 of the measurement unit 30, and the other end is connected to the second waste tank 32. When the three-way valve 281 is set to the above-described measurement state, a flow of the discharged liquid from the perfusate discharge pipe 28 to the second waste tank 32 via the three-way valve 281 occurs in the measurement pipe 31.

  A filter 33 is inserted in the measurement pipe 31. In the filter 33, solid components such as red blood cells and artificial red blood cells contained in the discharged liquid in the measurement pipe 31 are removed. Thereby, when measuring the absorbance in the absorbance measurement unit 34, it is possible to suppress the solid component from obstructing the accurate measurement of the absorbance.

  The absorbance measurement unit 34 is disposed closer to the second waste tank 32 than the filter 33 is. The absorbance measurement unit 34 measures the absorbance of the discharged liquid flowing in the measurement pipe 31 in a specific wavelength band. In this embodiment, in order to detect the concentration of ICG, the absorbance is measured using a laser beam having a center wavelength of 805 nm. The absorbance measuring section 34 has a light emitting section 341 and a light receiving section 342. The light emitting unit 341 and the light receiving unit 342 are arranged to face each other with the measurement pipe 31 interposed therebetween. The light in the specific wavelength band is emitted from the light emitting section 341 toward the measurement pipe 31 and the light receiving section 342. The light receiving section 342 receives light emitted from the light emitting section 341 and passing through the measurement pipe 31.

  The input display unit 70 has a role as an input unit for inputting a command signal from the outside to the control unit 80, and a role as a display unit for displaying a signal from the control unit 80. A touch panel is used for the input display unit 70 of the present embodiment. However, the input display unit 70 may include an input unit such as a keyboard or a mouse and a display unit such as a liquid crystal display.

  The control section 80 is a section for controlling the operation of each section in the ischemia time estimation device 1. As conceptually shown in FIG. 2, the control unit 80 of the present embodiment is configured by a computer having an arithmetic processing unit 801 such as a CPU, a memory 802 such as a RAM, and a storage unit 803 such as a hard disk drive. ing. The control unit 80 is electrically connected to the pump 23, the deaeration unit 24, the pressure gauge 25, the flow meter 26, the pump 29, the three-way valve 281, the absorbance measurement unit 34, and the input display unit 70, respectively.

  The control unit 80 temporarily reads the computer program P and the data D stored in the storage unit 803 into the memory 802, and the arithmetic processing unit 801 performs arithmetic processing based on the computer program P and the data D. The operation of each unit in the ischemia time estimation device 1 is controlled. Note that the control unit 80 may be configured by an electronic circuit.

  As shown in FIG. 2, the control unit 80 includes an operation control unit 81, an absorbance calculation unit 82, a marker concentration calculation unit 83, a decrease amount calculation unit 84, as function processing units realized as software by program processing by the CPU. It has an ischemia time estimation unit 85 and an estimation function calculation unit 86. The operation control unit 81 controls the operation of each unit of the ischemia time estimation device 1.

  The absorbance calculator 82 calculates the absorbance S82 from the intensity S34 of the light received by the light receiver 342. The marker concentration calculator 83 calculates the concentration S83 of ICG contained in the discharged liquid from the absorbance S82. The absorbance measurement unit 34, the absorbance calculation unit 82, and the marker concentration calculation unit 83 constitute a measurement unit 40 that measures the concentration S83 of ICG contained in the effluent discharged from the liver 9 in the measurement unit 30.

  The reduction amount calculating unit 84 calculates the ICG reduction amount S84 from the measurement result of the measuring unit 40, that is, the ICG concentration S83 calculated by the marker concentration calculating unit 83. The ischemia time estimation unit 85 estimates the ischemia time of the liver 9 from the estimation function S86 calculated by the estimation function calculation unit 86 in advance and the reduction amount S84 calculated by the reduction amount calculation unit 84, and S85 is output to the input display unit 70. Thus, the input display unit 70 displays the estimated ischemic time S85.

  The ischemia time is externally input to the estimation function calculation unit 86 for each of the plurality of livers 9 whose ischemia time is known. Further, for each of these livers 9, the reduction amount S84 calculated by the reduction amount calculating unit 84 is input. Thereby, the estimation function calculation unit 86 calculates the estimation function S86 indicating the relationship between the ischemic time and the amount of ICG reduction.

  Note that the control unit 80 does not have the estimation function calculation unit 86, and the ischemia time estimation unit 85 uses the estimation function input from the outside and the decrease amount S84 calculated by the decrease amount calculation unit 84 to calculate the liver 9 A configuration for estimating the ischemic time may be used.

<1-2. Flow of ischemia time estimation method>
Next, a method of estimating the ischemic time of the liver 9 using the ischemic time estimating apparatus 1 will be described with reference to FIG. FIG. 3 is a flowchart showing the flow of the ischemia time estimation method. FIG. 4 is a graph showing an example of the estimation function S86.

  First, an estimation function S86 is obtained (step ST100). The specific flow of step ST100 will be described later. The estimation function S86 in the example of FIG. 4 is a function in which the ICG decrease amount f (t) increases as the ischemia time t increases. Further, the estimation function S86 in the example of FIG. 4 is a function indicating the amount of decrease f (t) of the ICG as a linear function of the ischemia time t.

  First, after the target liver 9 whose ischemia time is to be estimated is set in the ischemia time estimation device 1, the operation control unit 81 starts perfusion by the perfusion unit 20 (step ST200).

  Then, after a lapse of a predetermined time from the start of perfusion, the operation control section 81 sets the three-way valve 281 to the measurement state and performs measurement by the absorbance measurement section 34 (step ST300). Here, FIG. 5 is a conceptual diagram showing the relationship between the elapsed time from the start of perfusion of the perfusion solution containing ICG and the decrease in ICG. As shown in FIG. 5, after a lapse of a predetermined time (about 40 minutes in the example of FIG. 5) from the start of perfusion, the amount of decrease in ICG falls within a certain range. For this reason, it is preferable to perform the measurement of the absorbance in step ST300 after 40 minutes from the start of perfusion.

  In step ST300, specifically, the operation control section 81 drives the light emitting section 341 to emit laser light. Then, the intensity S34 of the light received by the light receiving unit 342 is input to the absorbance calculating unit 82. The absorbance calculator 82 calculates the absorbance S82 from the intensity S34 of the light received by the light receiver 342. Thereafter, the marker concentration calculator 83 calculates the concentration S83 of ICG contained in the discharged liquid from the absorbance S82.

  Next, the reduction amount calculation unit 84 calculates the ICG reduction amount S84 from the ICG concentration S83 calculated by the marker concentration calculation unit 83 (step ST500).

  Before the start of perfusion in step ST200, the light intensity S34 of the perfusion solution containing no ICG and the perfusion solution containing ICG before being supplied to the liver is measured in the measurement unit 30 in advance. . The absorbance calculator 82, the marker concentration calculator 83, and the decrease calculator 84 calculate the absorbance S82, the ICG concentration S83, and the ICG decrease S84 based on these data.

  When the intensity S34 of the light received by the light receiving unit 342 is small, the value of the absorbance S82 calculated by the absorbance calculation unit 82 increases. As a result, the concentration S83 of ICG contained in the effluent, which is calculated by the marker concentration calculator, also becomes a large value. Then, the ICG reduction amount S84 calculated by the reduction amount calculation unit 84 is a small value. On the other hand, when the intensity S34 of the light received by the light receiving unit 342 is large, the value of the absorbance S82 calculated by the absorbance calculation unit 82 becomes small. Thus, the ICG density S83 calculated by the marker density calculation unit also becomes a small value. Then, the ICG reduction amount S84 calculated by the reduction amount calculation unit 84 becomes a large value.

  Thereafter, the ischemia time estimating unit 85 estimates the ischemic time of the liver 9 from the estimation function S86 acquired in step ST100 and the reduction amount S84 calculated by the reduction amount calculating unit 84 (step ST600). Specifically, based on the estimation function S86 shown in FIG. 4, the ischemia time t at which the reduction amount S84 calculated by the reduction amount calculating unit 84 and the reduction amount f (t) of the ICG coincide with each other is referred to. t is estimated as the ischemic time of the liver 9.

  As described above, it is possible to estimate the ischemic time of the extracted liver 9 using the biomarker ICG and the estimation function S86.

  Next, the process of acquiring the estimation function S86 in step ST100 will be described with reference to FIG. FIG. 6 is a flowchart showing a flow of the estimation function obtaining step included in the ischemia time estimation method. In step ST100, the estimation function S86 is acquired by acquiring the ICG reduction amount S84 for each of N (plural) test livers whose ischemic time is known.

  At the start of step ST100, control unit 80 sets count number n to n = 0. Then, as shown in FIG. 6, first, one of the test livers is set in the ischemia time estimation device 1 (step ST101).

  Then, as in steps ST200 to ST500, perfusion of the test liver is started (step ST102), and after a lapse of a predetermined time from the start of perfusion, the absorbance S82 and the concentration S83 of ICG are measured and calculated (step ST103). After stopping (step ST104), the ICG reduction amount S84 is calculated (step ST105).

  When the calculation of the ICG reduction amount S84 of the test liver in steps ST101 to ST105 is completed, the count number n is incremented (step ST106). Then, it is determined whether or not the count number n is equal to or greater than the number N of test livers (step ST107).

  If the count number n is less than the number N of test livers in step ST107, the process returns to step ST101, and steps ST101 to ST105 are performed for the next test liver.

  If the count number n has reached the number N of test livers in step ST107, that is, if the calculation of the ICG reduction amount S84 has been completed for all N test livers, the process proceeds to step ST108.

  Then, the estimation function calculation unit 86 calculates the estimation function S86 from the relationship between the ischemia times of the N test livers and the ICG reduction amount S84. Specifically, as shown in FIG. 4, the estimation function calculation unit 86 of the present embodiment calculates the estimation function f (t), the ICG reduction amount S84 by a linear function of the ischemia time t. Is calculated as The estimation function calculation unit 86 calculates the estimation function f (t) from the ischemia time for the N test livers and the calculated ICG reduction amount S84 using an approximation method such as the least square method. . The estimation function f (t) shown in FIG. 4 is a function in which the amount of decrease in ICG increases as the ischemia time t increases.

<1-3. Experimental example>
An experimental example of the estimation function acquisition step in step ST100 will be described below. FIG. 7 is a graph of the estimation function f (t) according to one experimental example. In this experimental example, steps ST102 to ST105 were performed on test livers of four pigs whose ischemic time t was known. In this experimental example, the ischemia time t is a warm ischemia time.

  As a result, as shown in FIG. 7, in the test liver with the ischemic time of 0 min, the reduction amount of ICG S84 is 0.255 μg / ml, and in the test liver with the ischemic time of 30 min, the reduction amount of ICG is 0.8 μg / ml. 388 μg / ml, the ICG reduction S84 was 0.496 μg / ml in the test liver with an ischemic time of 60 min, and the ICG reduction S84 was 0.919 μg / ml in the test liver with an ischemic time of 120 min. there were.

  When an approximation curve of a linear function is calculated for these four data by using the least squares method, an estimation function f (t) is calculated as f (t) = 0.0055t + 0.2235.

  As shown in FIG. 7, when estimating the warm ischemia time of the liver using ICG as a biomarker, it is considered appropriate to approximate the estimation function f (t) to a linear function of the ischemia time t. The estimation function f (t) is a function in which the amount of decrease in ICG increases as the ischemia time t increases.

  In this case, assuming that ICG reduction amount S84 calculated in step ST500 is 0.5 μg / ml, it is estimated in step ST600 that the warm ischemia time is about 51 minutes.

<2. Modification>
As described above, one embodiment of the present invention has been described, but the present invention is not limited to the above embodiment.

  In the above embodiments and modifications, the estimation function is calculated as a linear function of the ischemic time, but the present invention is not limited to this. The estimation function may be a quadratic function of ischemia time, a higher-order function of third order or higher, or another function such as an exponential function.

  In addition, the elements appearing in the above-described embodiments and the modified examples may be appropriately combined as long as no contradiction occurs.

DESCRIPTION OF SYMBOLS 1 Ischemic time estimation apparatus 9 Liver 20 Perfusion unit 21 Perfusate reservoir 30 Measurement unit 34 Absorbance measurement unit 40 Measurement unit 80 Control unit 81 Operation control unit 82 Absorbance calculation unit 83 Marker concentration calculation unit 84 Decrease amount calculation unit 85 Ischemic time Estimator 86 Estimation function calculator S34 Intensity S82 Absorbance S83 Concentration S84 Decrease S85 Estimated ischemia time S86 Estimation function

Claims (11)

An ischemia time estimation method for estimating the ischemia time of the removed organ,
a) perfusing the organ with a perfusion solution containing a biomarker;
b) measuring the concentration of the biomarker contained in the effluent discharged from the organ in the step a);
c) calculating the amount of decrease in the biomarker from the measurement result of the step b);
d) estimating the ischemia time of the organ from an estimation function indicating the relationship between the ischemia time and the decrease amount of the biomarker, and the calculation result of the step c);
Ischemic time estimation method. The method for estimating ischemic time according to claim 1, wherein before the step a),
e) perfusing a perfusion solution containing the biomarker with respect to the plurality of organs whose ischemia time is known;
f) measuring the concentration of the biomarker contained in the effluent discharged from each of the plurality of organs in the step e);
g) calculating the decrease amount of the biomarker for each of the plurality of organs from the measurement result of the step f);
h) calculating the estimation function from a relationship between the ischemic time of the plurality of organs and the decrease amount of the biomarker;
Ischemia time estimation method, further comprising: An ischemic time estimation method according to claim 1 or claim 2,
The organ is a liver,
The ischemic time estimation method, wherein the biomarker is indocyanine green. An ischemic time estimation method according to claim 3,
The ischemia time estimation method, wherein the ischemia time is a warm ischemia time.
Become) An ischemic time estimation method according to claim 3 or claim 4,
The ischemia time estimation method, wherein the estimation function is a function in which the decrease amount of the biomarker increases as the ischemia time increases. An ischemic time estimation method according to any one of claims 3 to 5,
The ischemia time estimation method, wherein the estimation function is a function indicating the amount of decrease in the biomarker by a linear function of the ischemia time. Ischemic time estimating device for estimating the ischemic time of the removed organ,
A perfusion unit for perfusing a perfusion solution containing a biomarker into the organ,
A measurement unit that measures the concentration of the biomarker contained in the effluent discharged from the organ in the perfusion unit,
From the measurement result of the measurement unit, a reduction amount calculation unit that calculates the reduction amount of the biomarker,
An estimation function indicating the relationship between the ischemic time and the decrease amount of the biomarker, and the decrease amount calculated by the decrease amount calculation unit, an ischemia time estimation unit that estimates the ischemia time of the organ. ,
An ischemia time estimating device comprising: The ischemia time estimation device according to claim 7,
The organ is a liver,
The ischemic time estimation device, wherein the biomarker is indocyanine green. An ischemic time estimation device according to claim 8,
The ischemia time estimation device, wherein the ischemia time is a warm ischemia time. An ischemic time estimation device according to claim 8 or claim 9,
The ischemia time estimation device, wherein the estimation function is a function in which the decrease amount of the biomarker increases as the ischemia time increases. An ischemia time estimation device according to any one of claims 8 to 10,
The ischemia time estimating device, wherein the estimation function is a function indicating the amount of decrease in the biomarker by a linear function of the ischemia time.